PT - JOURNAL ARTICLE AU - Vargas-Poussou, Rosa AU - Dahan, Karin AU - Kahila, Diana AU - Venisse, Annabelle AU - Riveira-Munoz, Eva AU - Debaix, Huguette AU - Grisart, Bernard AU - Bridoux, Franck AU - Unwin, Robert AU - Moulin, Bruno AU - Haymann, Jean-Philippe AU - Vantyghem, Marie-Christine AU - Rigothier, Claire AU - Dussol, Bertrand AU - Godin, Michel AU - Nivet, Hubert AU - Dubourg, Laurence AU - Tack, Ivan AU - Gimenez-Roqueplo, Anne-Paule AU - Houillier, Pascal AU - Blanchard, Anne AU - Devuyst, Olivier AU - Jeunemaitre, Xavier TI - Spectrum of Mutations in Gitelman Syndrome AID - 10.1681/ASN.2010090907 DP - 2011 Apr 01 TA - Journal of the American Society of Nephrology PG - 693--703 VI - 22 IP - 4 4099 - http://jasn.asnjournals.org/content/22/4/693.short 4100 - http://jasn.asnjournals.org/content/22/4/693.full SO - J. Am. Soc. Nephrol.2011 Apr 01; 22 AB - Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.